[Frontiers in Bioscience 2, d12-26, January 1, 1997]

CYTOKINES IN ACUTE AND CHRONIC INFLAMMATION

1
Carol A. Feghali, Ph.D., and Timothy M. Wright, M.D .

Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, E1109
Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Discussion
3.1 Cytokines involved in acute inflammation
3.1.1 Interleukin-1
3.1.2 Tumor necrosis factor
3.1.3 Interleukin-6
3.1.4 Interleukin-11
3.1.5 Interleukin-8/chemokines
3.1.6 Eotaxin
3.1.7 Interleukin-16
3.1.8 Interleukin-17
3.1.9 Colony stimulating factors
4. Cytokines involved in chronic inflammation
4.1.1 The humoral inflammatory response
4.1.1.1 Interleukin-3
4.1.1.2 Interleukin-4
4.1.1.3 Interleukin-5
4.1.1.4 Interleukin-7
4.1.1.5 Interleukin-9
4.1.1.6 Interleukin-10
4.1.1.7 Interleukin-13
4.1.1.8 Interleukin-14
Transforming growth factor-
4.1.2 The cellular inflammatory response
4.1.2.1 Interleukin-2
4.1.2.2 Interleukin-12
4.1.2.3 Interleukin-15
4.1.2.4 Interferons
4.1.2.5 IFN--inducing factor 51 Receptors of inflammatory
cytokines
6. Summary
7. References

1. ABSTRACT for chronic inflammation. This review describes the

Inflammation is mediated by a variety of
soluble factors, including a group of secreted
polypeptides known as cytokines. Inflammatory
cytokines can be divided into two groups: those
involved in acute inflammation and those responsible
Received11/6/96; Accepted 12/13/96
1
To whom correspondence should be addressed, at
Division of Rheumatology and Clinical Immunology,
Department of Medicine, University of Pittsburgh,
E1109 Biomedical Science Tower, 200 Lothrop St.,
Pittsburgh, PA 15261. Tel #: (412)624-9028; Fax #:
(412)648-7047. E-mail: Wright@novell1.dept-med.
pitt.edu; Feghali@novell1.dept-med.pitt.edu
role played in acute inflammation by IL-1, TNF-, IL-
6, IL-11, IL-8 and other chemokines, G-CSF, and
GM-CSF. It also describes the involvement of
cytokines in chronic inflammation. This latter group
can be subdivided into cytokines mediating humoral
responses such as IL-4, IL-5, IL-6, IL-7, and IL-13,
and those mediating cellular responses such as IL-1,
IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferons,
transforming growth factor-, and tumor necrosis
factor and . Some cytokines, such as IL-1,
significantly contribute to both acute and chronic
inflammation. This review also summarizes features
of the cell-surface receptors that mediate the
inflammatory effects of the described cytokines.

1
Role of cytokines in inflammation
2. INTRODUCTION
Inflammation, the response of tissue to
injury, is characterized in the acute phase by
increased blood flow and vascular permeability along
with the accumulation of fluid, leukocytes, and
inflammatory mediators such as cytokines. In the
subacute/chronic phase (hereafter referred to as the
chronic phase), it is characterized by the development
of specific humoral and cellular immune responses to
the pathogen(s) present at the site of tissue injury.
During both acute and chronic inflammatory
processes, a variety of soluble factors are involved in
leukocyte recruitment through increased expression of
cellular adhesion molecules and chemoattraction.
Many of these soluble mediators regulate the
activation of the resident cells (such as fibroblasts,
endothelial cells, tissue macrophages, and mast cells)
and the newly recruited inflammatory cells (such as
monocytes, lymphocytes, neutrophils, and
eosinophils), and some of these mediators result in
the systemic responses to the inflammatory process
(e.g. fever, hypotension, synthesis of acute phase
proteins, leukocytosis, cachexia). The soluble factors
that mediate these responses (reviewed in ref. 1) fall
into four main categories: (1) inflammatory lipid
metabolites such as platelet activating factor (PAF)
and the numerous derivatives of arachidonic acid
(prostaglandins, leukotrienes, lipoxins), which are
generated from cellular phospholipids; (2) three
cascades of soluble proteases/substrates (clotting,
complement, and kinins), which generate numerous
pro-inflammatory peptides; (3) nitric oxide, a potent
endogenous vasodilator, whose role in the
inflammatory process has only recently begun to be
explored; and (4) a group of cell-derived
polypeptides, known as cytokines, which to a large
extent orchestrate the inflammatory response, i.e.
they are major determinants of the make-up of the
cellular infiltrate, the state of cellular activation, and
the systemic responses to inflammation. Most
cytokines are multifunctional. They are pleiotropic
molecules that elicit their effects locally or
systemically in an autocrine or paracrine manner.
Cytokines are involved in extensive networks that
involve synergistic as well as antagonistic
interactions and exhibit both negative and positive
regulatory effects on various target cells.
This review will focus on inflammatory
cytokines, including a description of their primary
activities related to acute and chronic inflammation,
and a discussion of their cell surface receptors.
3. DISCUSSION
3.1 Cytokines involved in acute inflammation:
Several cytokines play key roles in
mediating acute inflammatory reactions, namely IL-1,
TNF-, IL-6, IL-11, IL-8 and other chemokines, G-
CSF, and GM-CSF (Figure 1). Of these, IL-1 ( and
) and TNF are extremely potent inflammatory
molecules: they are the primary cytokines that
mediate acute inflammation induced in animals by
intradermal injection of bacterial lipopolysaccharide
and two of the primary mediators of septic shock.
3.1.1 Interleukin-1:
The cDNAs for IL-1and were cloned in
1984. They are encoded by two different genes, both
located on human chromosome 2. Their size ranges
from 22-31 kDa for cell-associated molecules, and
17.5 kDa for the secreted molecule (2). Their main
cellular sources are mononuclear phagocytes,
fibroblasts, keratinocytes, and T and B lymphocytes.
Previous synonyms--endogenous pyrogen (EP),
mononuclear cell factor, and lymphocyte-activating
factor (LAF)--emphasize the role of IL-1 in
inflammation. Both IL-1and IL-1 can trigger fever
by enhancing prostaglandin E2 (PGE2) synthesis by
the vascular endothelium of the hypothalamus (2) and
can stimulate T cell proliferation. In addition, IL-1
elicits the release of histamine from mast cells at the
site of inflammation (Figure 2). Histamine then
triggers early vasodilation and increase of vascular
permeability. The pro-inflammatory effects of IL-1
can be inhibited by IL-1 receptor antagonist (IL-1Ra),
originally referred to as IL-1 inhibitor. IL-1Ra is
produced by immune complex- or IL-4-stimulated
macrophages and by TNF- or GM-CSF-stimulated
neutrophils. It bears approximately 20-25% homology
at the amino acid level to IL-1 and IL-1. IL-1Ra
inhibits IL-1 action by competing with IL-1 for
binding to the IL-1 receptor (IL-1R) (3,4).
3.1.2 Tumor necrosis factor:
Tumor necrosis factors-(TNF)and are
cytokines that bind to common receptors on the
surface of target cells and exhibit several common
biological activities. Human TNF-and TNF- are of
17 and 25 kDa, respectively. Their corresponding
cDNAs were cloned in 1984, and the genes encoding
the factors have been mapped to chromosome 6 in
humans (5), within the region of the major
histocompatibility complex (MHC). TNF-, or
cachectin, exists as a trimer (6) and is one of the
products of activated macrophages/monocytes,
fibroblasts, mast cells, and some T and natural killer
(NK) cells (7,8) (Figure 2). TNF-and IL-1 share
several pro-inflammatory properties. Like IL-1, TNF-
can induce fever, either directly via stimulation of
PGE2 synthesis by the vascular endothelium of the
hypothalamus, or indirectly by inducing release of IL-
1 (2). Both cytokines can stimulate the production of
collagenase and PGE2 by synovial cells and thus are
believed to contribute to joint damage in
inflammatory conditions such as rheumatoid arthritis
(2). TNF-also shares an important inflammatory
property with IL-6 and IL-11, i.e. the induction of
acute phase reactant protein production by the liver.
TNF-and IL-1 further exert secondary inflammatory
effects by stimulating IL-6 synthesis in several cell
types. IL-6 then mediates its
FIGURE 1: Cytokines involved in acute and chronic inflammatory responses.
own effects and those of TNF-and IL-1 in inducing
fever and the acute phase response (2), thereby
perpetuating the inflammatory response through a
cascade of cytokines with overlapping properties.
TNF-, also known as lymphotoxin, is
produced by activated T and B lymphocytes. It binds
to the same high affinity receptors as TNF-. Its
properties are similar to those of TNF- and include
the induction of apoptosis (programmed cell death) in
many types of transformed, virally infected, and
tumor cells, and the stimulation of several PMN
effector functions (9).
Although in general the effects of cytokines
are exerted locally at the site of their production
(autocrine and paracrine), TNF-and TNF-, as well
as IL-1 and IL-6, have major systemic (endocrine)
effects when either produced acutely in large
amounts, as in the case of bacterial sepsis, or
chronically in lesser amounts, as in the case of
chronic infections. During sepsis with Gram negative
organisms, lipopolysaccharides (endotoxin) released
from bacteria trigger the widespread production of
TNF-(and subsequently IL-1 and IL-6) by
macrophages. The systemic release of these cytokines
has been shown to be responsible for the fever and
hypotension that characterize septic shock (8). In an
analogous fashion, the production of large amounts of
TNF-by T lymphocytes in response to
"superantigens" such as staphylococcal toxic shock
syndrome toxin and enterotoxins are responsible for
many of the systemic manifestations (fever,
hypotension) of infections with toxin-producing Gram
positive organisms (10,11). In addition, the chronic
production of TNF is believed to be responsible for
the metabolic alterations which result in the cachexia
associated with chronic parasitic infections and some
cancers (8).
3.1.3 Interleukin-6:
Previous synonyms of IL-6 illustrate some
of its biologic activities. They include interferon-2
(IFN-2), hybridoma/plasmacytoma growth factor,
hepatocyte-stimulating factor, B cell stimulatory
factor 2 (BSF-2), and B cell differentiation factor
(BCDF). IL-6 is a glycoprotein ranging from 21 to 28
kDa depending on the degree of post-translational
modification. The IL-6 cDNA was cloned in 1986 and
the gene encoding IL-6 was mapped to chromosome 7
in humans (12). IL-6 is produced by a variety of cells
including mononuclear phagocytes, T cells, and
fibroblasts (12-14). In addition to the stimulation of
acute phase protein synthesis by the liver, IL-6 acts as
a growth factor for mature B cells and induces their
final maturation into antibody-producing plasma
cells. It is involved in T cell activation and
differentiation, and participates in the induction of IL-
2 and IL-2 receptor expression (Figure 2). Some of
the regulatory effects of IL-6 involve inhibition of
TNF production, providing negative feedback for
limiting the acute inflammatory response.
Upregulation of IL-6 production has been observed in
a variety of chronic inflammatory and autoimmune
disorders such as thyroiditis, type I diabetes,
rheumatoid arthritis (15,16), systemic sclerosis (17),
mesangial proliferative glomerulonephritis and
psoriasis, and neoplasms such as cardiac myxoma,
renal cell carcinoma, multiple myeloma, lymphoma,
and leukemia (15).
3.1.4 Interleukin-11:
IL-11 is a cytokine of 24 kDa encoded by a
gene located on the long arm of chromosome 19. The
corresponding cDNA was cloned in 1990 (18). IL-11
FIGURE 2: Inflammatory cytokines, their primary sources and target cells. *IFN- stimulates IgG2 production in
the mouse.

is produced by bone marrow stromal cells and by
some fibroblasts. It is a functional homologue of IL-6
and can replace IL-6 for the proliferation of certain
plasmacytoma cell lines (18) and in the induction of
acute phase protein secretion in the liver (19).
Additional IL-11 activities include stimulation of T
cell-dependent B cell immunoglobulin secretion,
increased platelet production, and induction of IL-6
+
expression by CD4 T cells.
 3.1.5 Interleukin-8/chemokines:
IL-8 and other low molecular weight
chemokines (e.g. platelet factor 4, IP-10, mig, ENA-
78, macrophage inflammatory protein (MIP)-1 and
, MIP-2, monocyte chemoattractant protein-1 (MCP-
1/JE), RANTES) belong to a chemotactic cytokine
family and are responsible for the chemotactic
migration and activation of neutrophils and other cell
types (such as monocytes, lymphocytes, basophils,
and eosinophils) at sites of inflammation (20,21). The
two subsets of the chemokine family, CXC (or ),
C-C (or ) are divided based on presence or
absence of an amino acid between the first two of
four conserved cysteines. A recent third subset, C,
has only two cysteines and to date only one member,
IL-16, has been identified (22). Chemokines have
been implicated in inflammatory conditions from
acute neutrophil-mediated conditions such as acute
respiratory distress syndrome to allergic asthma,
arthritis, psoriasis, and chronic inflammatory
disorders. To date, at least 27 chemokines have been
described. The product of many cell types, including
mononuclear phagocytes, antigen-activated T cells,
endothelial and epithelial cells, and even neutrophils,
IL-8 was previously known as neutrophil chemotactic
factor (NCF) and neutrophil activating protein (NAP-
1) (20,23). It is the most thoroughly studied
chemokine and therefore serves as a prototype for
discussing the biologic properties of this rapidly
growing family of inflammatory mediators. It consists
of a 6-8 kDa protein whose cDNA was cloned by
three different laboratories between 1987 and 1989.
The corresponding gene has been mapped to
chromosome 4 in humans (24). Its main inflammatory
impact lies in its chemotactic effects on neutrophils
and its ability to stimulate granulocyte activity. In
addition, IL-8, IL-1, and TNF are involved in
neutrophil recruitment by upregulating cell-surface
adhesion molecule expression (such as endothelial
leukocyte adhesion molecule, ELAM-1, and
intracellular adhesion molecule, ICAM-1), thereby
enhancing neutrophil adherence to endothelial cells
(2) and facilitating their diapedesis through vessel
walls. Thus, IL-8 mediates the recruitment and
activation of neutrophils in inflamed tissue (25). IL-8
can be detected in synovial fluid from patients with
various inflammatory rheumatic diseases (26), and
mucosal levels of IL-8 are elevated in patients with
active ulcerative colitis (27).
Other members of this cytokine family,
such as NAP-2, GRO, GRO, GRO, ENA-78,
RANTES, MCP-1, MCP-2, MCP-3, platelet factor 4,
MIP-1/, and MIP-2, are also likely to play
important roles in acute inflammation via their shared
effects on cell migration. MCP-1 is a chemokine
identified in supernatants of blood mononuclear cells.
Its production in monocytes is enhanced by
inflammatory cytokines. MIP-1 and MIP-1 induce its gene was mapped to chromosome 5 in humans
monocyte and T lymphocyte migration. MIP-1,
MCP-1, and MIP-2 have been implicated in the
pathogenesis of rheumatoid arthritis where they are
believed to recruit mononuclear cells into the
inflamed regions of the synovium (28). Several other
members of the IL-8/chemokine family have been
identified but their biologic effects are as yet poorly
defined. Two recently identified chemokines, eotaxin
and IL-16, have some unique properties and are
described below.
3.1.6 Eotaxin:
Eotaxin was initially described in rodent
models of asthma. The human homolog has since
been cloned and consists of a 74-amino acid protein.
Eotaxin has two of four adjacent cysteines which are
highly conserved among (C-C) chemokines. At the
amino acid level, it is most homologous to the MCP
proteins. Eotaxin is a specific chemoattractant for
eosinophils. It is produced by cytokine-stimulated
epithelial and endothelial cells as well as IL-3-
stimulated eosinophils. Eotaxin is implicated in
inflammatory bowel disease where its mRNA levels
are markedly elevated, especially in ulcerative colitis
(29)
3.1.7 Interleukin-16:
IL-16 was originally identified as a
chemotactic factor known as lymphocyte
chemoattractant factor or lymphotactin. It is the only
member of the C family of chemokines. The gene
encoding IL-16 has been mapped to human
chromosome 1 (22). IL-16 is an unusual cytokine in
that preformed IL-16 is stored in CD8+ lymphocytes
and is secreted upon stimulation with histamine or
serotonin (30). It induces chemotaxis of CD4+ T
lymphocytes (31,32) (Figure 2) and is believed to
initiate T-cell mediated inflammation in asthma (33).
3.1.8 Interleukin-17:
The human IL-17 cDNA was cloned in
1995 based on homology with murine CTLA8 (34). A
1.9 Kb cDNA was found to encode a protein of 17.5
kDa homologous to a product of Herpesvirus saimiri
(HVS13) (34). IL-17 is a product of activated T
lymphocytes and its biologic activities include
stimulation of IL-6 and IL-8 production and enhanced
ICAM-1 expression on human foreskin fibroblasts
(34).
3.1.9 Colony stimulating factors:
Colony stimulating factors (CSF) are named
according to the target cell type whose colony
formation in soft agar cultures of bone marrow they
induce (35). Of the CSF's, granulocyte-CSF (G-CSF)
and granulocyte macrophage-CSF (GM-CSF)
participate in acute inflammation. G-CSF was cloned
in 1986 and its gene was mapped to chromosome 17
(36). It is a non-glycosylated protein of 19 kDa
molecular weight. GM-CSF is a 22 kDa protein. Its
full length cDNA sequence was obtained in 1985 and
(36). Monocytes, T cells, fibroblasts and endothelial
cells activated by macrophage products such as IL-1
or TNF, can produce G-CSF and GM-CSF. Both
 CSF's can stimulate neutrophils, while GM-CSF can
also activate effector functions of eosinophils and
mononuclear phagocytes (Figure 2). An example of
the pathophysiologic role of GM-CSF is the airway
inflammation accompanying asthma, where the
implicated cytokines include IL-3, IL-5, and GM-CSF
which perpetuate eosinophil activation and survival.
In this scenario, the source of GM-CSF may be the
alveolar macrophages which are reported to produce
two to threefold higher levels of GM-CSF than
control macrophages (37). Another possible source
for all three cytokines are T cells present in the
airways. Additional cytokines such IL-4, IL-13 (both
stimulatory) and IFN- (inhibitory) may be involved
in the control of IgE synthesis, while IL-1 and TNF-
may contribute to the airway inflammation by
upregulation of endothelial adhesion molecule
expression (37).
4. CYTOKINES INVOLVED IN CHRONIC
INFLAMMATION:
Chronic inflammation may develop
following acute inflammation and may last for weeks
or months, and in some instances for years. During
this phase of inflammation, cytokine interactions
result in monocyte chemotaxis to the site of
inflammation where macrophage activating factors
(MAF), such as IFN-, MCP-1, and other molecules
then activate the macrophages while migration
inhibition factors (MIF), such as GM-CSF (38) and
IFN-, retain them at the inflammatory site. The
macrophages contribute to the inflammatory process
by chronically elaborating low levels of IL-1 and TNF
which are responsible for some of the resulting
clinical symptoms such as anorexia, cachexia, fever,
sleepiness, and leukocytosis.
The cytokines known to mediate chronic
inflammatory processes can be divided into those
participating in humoral inflammation, such as IL-3,
IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, and
transforming growth factor- (TGF-), and those
contributing to cellular inflammation such as IL-1, IL-
2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferons
(IFNs), IFN- inducing factor (IGIF), TGF-, and
TNF-and -(Figure 1).
4.1.1 Cytokines primarily involved in the humoral
inflammatory response:
4.1.1.1 Interleukin-3:
IL-3, also called multi-CSF, is produced by
activated T cells and mast cells. The molecular
weight of IL-3 ranges from 14 to 36 kDa. The cloning
of the corresponding cDNA was reported in 1984, and
the IL-3 gene has been localized to chromosome 5
(39). It stimulates eosinophils and B cell
differentiation while it inhibits lymphokine-activated
killer (LAK) cell activity (40) (Figure 2). IL-3 shares
several biological activities with GM-CSF (41).
4.1.1.2 Interleukin-4:
IL-4 is expressed as a 15-19 kDa protein
and exists as a dimer. The IL-4 gene has been
mapped to human chromosome 5, and the
corresponding cDNA was cloned in 1986 (42,43). IL-
+
4 is produced by CD4 (TH) cells, mast cells, and
+
basophils. It induces CD4 T cells to differentiate into
TH2 cells while suppressing the development of TH1
cells. It also acts as a B cell, T cell, and mast cell
growth factor, it enhances class II MHC expression
on B cells, and it promotes immunoglobulin class
switching to IgG1 and IgE (42,43) (Figure 2). In fact,
IL-4 is necessary for IgE response induction, and its
absence also leads to significantly lower levels of
IgG1 in T cell-dependent immune responses (44). The
stimulatory effects of IL-4 on IgG1 and IgE production
and on MHC class II induction are downregulated by
IFN-, a cytokine whose functions are antagonized by
IL-4 and vice versa. IL-4 also stimulates collagen (45)
and IL-6 production (46) by human dermal
fibroblasts, and may thus play a role in the
pathogenesis of fibrotic diseases such as systemic
sclerosis. In rheumatoid arthritis, on the other hand,
IL-4 appears to exhibit some anti-inflammatory
properties by inhibiting the production of several pro-
inflammatory cytokines such as IL-1, IL-6, IL-8, and
TNF-, by synovial membranes of rheumatoid
arthritis patients (47).
4.1.1.3 Interleukin-5:
Cloned in 1987, the IL-5 cDNA encodes a
protein of 20-22 kDa which has an apparent
molecular weight of 45 kDa upon dimerization. Like
IL-4, the gene for IL-5 has also been mapped to
chromosome 5 in humans (43). IL-5, also known as B
cell growth factor II (BCGFII) and T cell replacing
+
factor (TRF), is produced by CD4 T helper cells as
well as NK cells, and exists as a dimer linked by
disulfide bonds (40). IL-5 is involved in eosinophil
differentiation and activation and stimulation of
immunoglobulin class switching to IgA. Other
properties of IL-5 include increased activation of B
cell proliferation, and enhancement of T cell
cytotoxicity (43). The combined production of IL-4
+
and IL-5 by CD4 TH2 cells therefore results in IgE
and IgA production and mast cell and eosinophil
stimulation.
4.1.1.4 Interleukin-7:
IL-7 is a cytokine of about 25 kDa whose
cDNA was cloned in 1989. Its gene has been mapped
to human chromosome 8 (48). IL-7, a cytokine
purified as a pre-B cell growth factor, is a bone
marrow and thymic stromal cell product. It stimulates
the development of pre-B and pre-T cells and acts as
a growth factor for B cells, T cells, and early
thymocytes (48) (Figure 2).
4.1.1.5 Interleukin-9:
IL-9 is another cytokine produced by CD4+
T helper (TH2) cells as well as some B lymphomas.
First described in the mouse, IL-9 was known as mast
cell growth-enhancing activity (MEA) and murine T-
cell growth factor P40 (49). The IL-9 cDNA was
cloned in 1989 (50) and the gene encoding it was
mapped to human chromosome 5 (51). Its production
is IL-4 and IL-10, and thus IL-2-dependent. IL-9 is
regulatory in nature in that it inhibits lymphokine
production by IFN--producing CD4+ T cells and
enhances the growth of CD8+ T cells (52). In
addition, IL-9 promotes the production of
immunoglobulins by B cells and the proliferation of
mast cells (53).
4.1.1.6 Interleukin-10:
IL-10 is also referred to as B cell-derived T
cell growth factor and cytokine synthesis inhibitory
factor (CSIF) because it inhibits IFN- production by
activated T cells. The cDNA for human IL-10 was
cloned in 1990 and found to encode an 18 kDa
protein. IL-10 is produced by a variety of cell types,
+ +
including CD4 T cells, activated CD8 T cells, and
activated B cells (54). Its effects include reduction of
antigen-specific T cell proliferation, inhibition of IL-
2-induced IFN- production by NK cells, and
inhibition of IL-4 and IFN- induced MHC class II
expression on monocytes (55). Since IL-10 can be
produced by TH2 cells and inhibits TH1 function by
preventing TH1 cytokine production (such as IFN-),
IL-10 is considered a T cell cross-regulatory factor
and has thus been referred to as an "anticytokine"
(56). IL-10 also acts as a co-differentiation factor for
cytotoxic T cells and a co-factor for T cell growth.
Human IL-10 (hIL-10) shares 84% identity at the
amino acid level with a homolog, viral IL-10 (vIL-
10), which is encoded by the Epstein-Barr virus (57).
vIL-10 shares with hIL-10 inhibitory effects on
cytokine production and stimulatory effects on B cell
growth (58).
4.1.1.7 Interleukin-13:
IL-13 was originally identified as a protein
produced by activated murine TH2 lymphocytes and
referred to as P600 (59). The cDNA for IL-13 was
recently cloned and the gene was mapped to human
chromosome 5, closely linked to the gene encoding
IL-4 (60). A 12-17 kDa protein, IL-13 exhibits anti-
inflammatory activities by inhibiting the production
of inflammatory cytokines, such as IL-1, TNF-, IL-
8, and IL-6, by human peripheral blood monocytes
induced with lipopolysaccharide (60). Inhibition of
inflammatory cytokine production is also a
characteristic of two other cytokines produced by TH2
lymphocytes, namely IL-4 and IL-10. In addition, IL-
13 enhances monocyte and B lymphocyte
differentiation and proliferation, increases CD23
expression, and induces IgG4 and IgE class switching
(61).
4.1.1.8 Interleukin-14:
A product of malignant B and T cells as
well as normal T cells, IL-14 is a 53 kDa B-cell
growth factor (BCGF). Like IL-4, IL-14 has been
shown to induce B cell proliferation. However, IL-14
inhibits immunoglobulin secretion (53). It has been
suggested to play an important role in the aggressive
form of B-cell type non-Hodgkins lymphoma (62).
4.1.1.9 Transforming growth factor-:
The transforming growth factor- (TGF-)
family of cytokines includes three isoforms, TGF-1,
2, and 3 which are encoded by separate genes yet
bind to the same high affinity receptor. TGF-
functions as a 25 kDa homodimer consisting of two
12-kDa polypeptides (63). The human cDNA for
TGF-1 was cloned in 1985 (64). It is produced by T
cells, platelets, and monocytes. TGF- inhibits T cell
and NK cell proliferation and activation (Figure 2)
and may play an important role in inflammation (64).
At a site of injury, TGF- stored in platelets is
released upon degranulation. TGF- then attracts
monocytes and other leukocytes to the site, thus
participating in the initial step of chronic
inflammation. TGF- then positively regulates its
own production and the production and deposition of
extracellular matrix components as well as the
expression of integrins resulting in enhanced cell
adhesion. It also inhibits collagenase production, and
if expression is prolonged, it may result in
progressive fibrosis analogous to unregulated tissue
repair. Conditions in which a role for TGF-has been
suggested include mesangial proliferative
glomerulonephritis and diabetic nephropathy in rats,
pulmonary fibrosis, and systemic sclerosis (63).
Another example of the role played by TGF- in
inflammation is collagen-induced arthritis in rats. In
this model, TNF-and TGF-, when injected into
the rat ankle joint, accelerate disease onset (65).
4.1.2 Cytokines involved primarily in the cellular
inflammatory response:
4.1.2.1 Interleukin-2:
The human IL-2 cDNA was cloned in 1983
and the corresponding gene has been mapped to the
long arm of chromosome 4 (66). IL-2 is a 15 kDa
glycoprotein originally known as T cell growth factor
(TCGF). It is secreted mainly by activated T helper
cells. It acts as a growth factor/activator for T cells,
NK cells, and B cells and promotes the development
of lymphokine-activated killer (LAK) cells (40,53)
(Figure 2). It therefore plays a critical role in
regulating both cellular and humoral chronic
inflammatory responses. Binding of IL-2 to the IL-2
receptor on T lymphocytes leads to cell proliferation,
increased lymphokine secretion (IFN-, lymphotoxin,
IL-4, IL-3, IL-5, GM-CSF), and enhanced expression
of class II MHC molecules.
4.1.2.2 Interleukin-12:
IL-12, previously known as natural killer
cell stimulatory factor (NKSF) and cytotoxic
lymphocyte maturation factor (CLMF), was originally
isolated from Epstein-Barr virus transformed B cells.
It is a heterodimer composed of two subunits of 35
and 40 kDa. The cDNAs for both subunits were
cloned in 1991 (67). Its biological activities include
enhancement of cytotoxic T cells and lymphokine-
activated killer (LAK) cell generation and activation,
increased natural killer (NK) cell cytotoxicity,
induction of activated T cell and NK cell
proliferation, induction of IFN-production by NK
cells and T cells, and inhibition of IgE synthesis by
IL-4-stimulated lymphocytes via IFN--dependent and
independent mechanisms (67-69) (Figure 2). IL-12 is
secreted by activated B cells, macrophages, and other
antigen-presenting cells (APCs), but its production is
inhibited by IL-4 and IL-10. In addition, the
stimulatory effect of IL-12 on TH1 development is
antagonized by IL-4, a cytokine which promotes TH2
cell development. Therefore, IL-12 plays an important
role in cell-mediated inflammation and also
contributes to the regulation of immunoglobulin
production.
4.1.2.3 Interleukin-15:
IL-15 is a cytokine of approximately 15 kDa
originally discovered as a T cell stimulatory activity
(70) produced by activated monocytes, epithelial
cells, and fibroblasts. IL-15 shares many biologic
properties with IL-2 and mediates its activity via a
multi-subunit high affinity receptor comprised of a
unique alpha chain and the beta and gamma chains of
the IL-2R. The human IL-15 gene has been mapped to
chromosome 4 (70), similarly to IL-2. However, IL-15
does not exhibit any sequence homology with IL-2.
IL-15 is produced by a large variety of cells including
T lymphocytes and monocytes. It stimulates T
lymphocyte and NK cell proliferation, as well as CTL
and LAK activity (53). It enhances B cell expansion
and immunoglobulin production (71) (Figure 2). It is
also a T lymphocyte chemoattractant. IL-15 may be
responsible for the recruitment and activation of T
lymphocytes in the synovium of patients with
rheumatoid arthritis where its levels have been found
to be elevated (72).
4.1.2.4 Interferons:
The interferons are a group of cytokines
originally identified by and named for their anti-viral
activity (73). Their corresponding cDNAs were
cloned in 1980-81. Type I interferons include IFN-,
an 18-20 kDa product of leukocytes, and IFN-, a
product of fibroblasts. They exhibit anti-viral as well
as anti-proliferative properties and upregulate MHC
class I expression. IFN-is encoded by several genes
clustered in the short arm of chromosome 9.
However, only one gene, also localized to
chromosome 9, codes for IFN- . Type II interferon,
immune interferon or IFN-, is a homodimer
produced by activated T cells and NK cells. A single
gene located on chromosome 12 encodes human IFN-
which has a molecular weight of 20 or 25 kDa
(monomer) depending on the extent of glycosylation
(74). IFN- is known to enhance MHC class I and II
expression on nucleated cells and to stimulate many
of the effector functions of mononuclear phagocytes.
While IFN-and - bind to a common receptor, IFN-
recognizes a distinct and specific cell surface
receptor. IFN- has been implicated in the
pathogenesis of a variety of autoimmune and chronic
inflammatory conditions (75) including murine
models of systemic lupus erythematosus (76), Type I
diabetes mellitus (77,78), adjuvant-induced arthritis
(79), and experimental cerebral malaria (80). Based
on experiments with IFN-knock-out mice, one of its
primary functions in vivo appears to be the activation
of macrophages to kill intracellular pathogens such as
Mycobacteria (81).
4.1.2.5 IFN--inducing factor:
An IFN--inducing activity was identified in
murine Kupffer cells and activated macrophages and
referred to as IFN--inducing factor (IGIF) (82). IGIF
induces IFN-production more potently than does IL-
12 and is involved in the development of TH1 cells.
The human homolog has been recently described and
shares functions with the murine cytokine such as the
induction of IFN- production by stimulated PBMC
and the enhancement of NK cell cytotoxicity (83). In
addition, human IGIF augments GM-CSF production
and decreases IL-10 production. It has been proposed
that IGIF be designated as Interleukin-18 (IL-18)
(83).
5. RECEPTORS OF INFLAMMATORY
CYTOKINES
Cytokines elicit their responses by binding
to specific high affinity cell-surface receptors on
target cells and initiating a series of intracellular
signal transduction pathways. The receptors of
several cytokines and growth factors are homologous
within their extracellular domains. These receptors
have been grouped into families, the largest of which
is the hematopoietin receptor superfamily which
includes one or multiple chains of the receptors for
erythropoietin, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9,
IL-11, IL-12, IL-13, IL-15, v-mpl oncogene, GM-CSF,
G-CSF, prolactin, and growth hormone. The receptors
in this family share a common motif of four conserved
cysteine residues in the amino-terminal portion of the
ligand-binding domain, as well as a conserved stretch
of amino acids (WSXWS = Trp-Ser-X-Trp-Ser; X
representing a nonconserved residue) proximal to
the membrane-spanning region. The receptors also
share fibronectin type III domains (84) (Figure 3).
Of the above-mentioned members of the
erythropoietin receptor family, one of the best
characterized is the IL-2 receptor (IL-2R). It consists
of three polypeptide chains: IL-2R (p70) and IL-2R
(p64), which are expressed on resting T cells, and IL-
2R(p55; T cell activation antigen or Tac), which is
expressed upon T cell activation. Association of these
subunits yields a high affinity receptor for IL-2
(85,86). In addition, Tac (IL-2R) is shed from cells
in a soluble form, but it has low affinity for IL-2.
Soluble IL-2R are elevated in the sera of patients
FIGURE 3: Common motifs shared by the erythropoietin receptor family.
with chronic inflammatory disorders such as
rheumatoid arthritis and systemic lupus
erythematosus (SLE) and the serum levels of soluble
IL-2R are reported to correlate with clinical disease
activity (87).
Another member of the erythropoietin
receptor family, IL-6 receptor (IL-6R), consists of an
80 kDa ligand-binding molecule and a 130 kDa non-
ligand binding signal-transducing subunit (gp130).
Both molecules exhibit the motifs shared by members
of the hematopoietin receptor superfamily (14,88).
Such a bimolecular complex is also described for IL-
3R, IL-5R, and GM-CSFR. For these receptors, the
polypeptide beta c (KH97) is reported to be the
accessory molecule (84). One of the biologic
consequences of these receptor complexes is that
although cytokines bind to specific receptors, some
may share common pathways in eliciting the target
cell's response as a result of shared receptor
components. As an example, IL-6, IL-11, leukemia
inhibitory factor (LIF), and oncostatin M recognize
different cellular receptors (by virtue of unique ligand-
binding subunits), but share the same signal-
transducing receptor subunit (gp130) and similar
biological activities (Figure 4). These cytokines may
therefore exert their effects via common signal
transduction pathways (84).
A group of receptors distantly related to the
erythropoietin receptor family consists of the
receptors for type I ( and ) and type II ()
interferons (89). Receptors in this class share a
homologous binding domain of about 210 amino acids
and four cysteine pairs divided equally between the
amino and carboxy termini.
Another group of related receptors includes
the two receptors for TNF, the receptor for nerve
growth factor (NGF), a transmembrane protein, FAS
(Apo-1 or CD95), involved in the apoptosis of
activated T lymphocytes (90), and CD40, a cell
surface receptor important in B cell growth and
isotype switching (91). The TNF receptors are 55
kDa (TR55) and 75 kDa (TR75) proteins that bind
TNF-and equally. Their extracellular domains
share 28% identity. There is growing evidence that
the two receptors may mediate different cellular
responses to TNF (92,93), although there may be
crosstalk between the receptors, perhaps at the level
of the signalling pathways to which they are coupled.
The chemokine receptors are members of
the G protein-coupled receptor (GPCR) superfamily
and include IL-8R-A, an IL-8-specific receptor, IL-
8R-B, a receptor recognized by IL-8, and other
chemokines of the CXC subset. Recently,
receptors for the CC subset of chemokines have been
identified. They include CC-CKR-1, CC-CKR-2, CC-
CKR-3,and CC-CKR-4 and CC-CKR-5 (94). A
recently described receptor, the Duffy blood group
antigen receptor for chemokines (DARC), binds both
CXC and CC chemokines. In addition, the
identification of new orphan chemokine receptors,
for which no ligands have been identified, has been
reported (95). Recently, five groups reported that CC-
CKR-5 is a co-receptor for certain strains of HIV-1
(96). A 32-bp deletion in CKR5 is reported to delay
progression to AIDS in infected individuals and may
be responsible for the antibody-negative status of
individuals exposed to HIV-1 (97).
FIGURE 4: Receptors (ligand-binding subunit) and accessory molecules (non-ligand-binding signal-transducing
subunit). Abbreviations: IL = Interleukin; LIF = Leukemia inhibitory factor; OSM = Oncostatin M; CNTF = Ciliary
neurotrophic factor; GM-CSF = Granulocyte macrophage colony stimulating factor.

receptors. Better understanding of the pathways

6. SUMMARY
In summary, cytokines are key modulators
of inflammation. They participate in acute and
chronic inflammation in a complex network of
interactions. Several cytokines exhibit some
redundancy in function and share overlapping
properties as well as subunits of their cell surface
regulated by cytokines will allow the identification
and/or development of agents for improved
modulation of the inflammatory response for the
treatment of autoimmune, infectious, and neoplastic
diseases.
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